Posgrado en Ciencias Químico Biológicas, Facultad de Química, Universidad Autónoma de Querétaro, Cerro de las Campanas S/N, Querétaro 76010, Mexico.
Facultad de Química, Universidad Autónoma de Querétaro, Centro Universitario, Querétaro 76010, Mexico.
Medicina (Kaunas). 2022 May 24;58(6):695. doi: 10.3390/medicina58060695.
: The multidrug resistance protein 4 (MRP4) is a member of the ABC transporter, which has been extensively related to many types of cancer including leukemia. MRP4 overexpression and activity over the efflux of some chemotherapeutic drugs are the main causes of chemoresistance. 6-mercaptopurine (6-MP) is a chemotherapeutic drug widely used in the consolidation and maintenance phases of leukemia treatment. However, 6-MP is a substrate of MRP4, which decreases its chemotherapeutic efficacy. Current research is focused on the development of MRP4 inhibitors to combat chemoresistance by allowing the accumulation of the drug substrates inside the cells. To date, the only specific MRP4 inhibitor that has been developed is ceefourin-1, which has been reported to inhibit MRP4 in many cancer cells and which makes it an excellent candidate to enhance the activity of 6-MP in a combined treatment in vitro of leukemic cells. in the present work, we determined the enhancing activity of ceefourin-1 on the antiproliferative and apoptotic effect of 6-MP in leukemic Jurkat cells by trypan blue assay and flow cytometry. Besides, we determined the 6-MP and ceefourin-1 binding sites into MRP4 by molecular docking and molecular dynamics. ceefourin-1 enhanced the apoptotic activity of 6-MP in Jurkat cells, while in CRL-1991 cells both antiproliferative and apoptotic effect were significantly lower. Ceefourin-1 additively cooperates with 6-MP to induce apoptosis in leukemic cells, but normal lymphoblast CRl-1991 showed resistance to both drugs. ceefourin-1 and 6-MP cooperates to trigger apoptosis in leukemic Jurkat cells, but the full mechanism needs to be elucidated in further works. In addition, our perspective is to test the cooperation between ceefourin-1 and 6-MP in samples from patients and healthy donnors.
多药耐药蛋白 4（MRP4）是 ABC 转运蛋白的成员，与包括白血病在内的多种类型的癌症广泛相关。MRP4 过度表达和活性导致一些化疗药物的外排，是化疗耐药的主要原因。6-巯基嘌呤（6-MP）是一种广泛用于白血病治疗巩固和维持阶段的化疗药物。然而，6-MP 是 MRP4 的底物，降低了其化疗效果。目前的研究集中在开发 MRP4 抑制剂上，通过允许药物底物在细胞内积累来对抗化疗耐药性。迄今为止，唯一开发的特异性 MRP4 抑制剂是 ceefourin-1，它已被报道在许多癌细胞中抑制 MRP4，使其成为增强 6-MP 在体外联合治疗白血病细胞活性的优秀候选药物。在本工作中，我们通过台盼蓝法和流式细胞术测定了 ceefourin-1 对白血病 Jurkat 细胞中 6-MP 抗增殖和促凋亡作用的增强活性。此外，我们通过分子对接和分子动力学确定了 6-MP 和 ceefourin-1 在 MRP4 中的结合位点。ceefourin-1 增强了 6-MP 在 Jurkat 细胞中的促凋亡活性，而在 CRL-1991 细胞中，其抗增殖和促凋亡作用均显著降低。ceefourin-1 与 6-MP 联合作用诱导白血病细胞凋亡，但正常淋巴细胞 CRL-1991 对两种药物均有耐药性。ceefourin-1 和 6-MP 合作触发白血病 Jurkat 细胞凋亡，但需要进一步的工作来阐明其完整的机制。此外，我们的观点是在患者和健康供体的样本中测试 ceefourin-1 和 6-MP 的合作。
